The emergence of ZDV-resistant HIV-1 in patients on chronic ZDV therapy is likely to have important clinical impact on the care of HIV-positive individuals. The clinical significance of ZDV-resistant HIV-1 is uncertain, but with other viruses, such as herpes simplex and cytomegalovirus resistance is clearly clinically relevant. Recent evidence suggests that subtle changes in the molecular structure of drug-resistant HIV-1 reverse transcriptase have direct effects on the DNA polymerase and ribonuclease functions of the reverse transcriptase protein. The major training goal of this Physician Scientist Award is to provide the physician-applicant with further training in the concepts and methods of the molecular biology of HIV-1 in order to provide a firm foundation to build an independent laboratory-based career. The major research goals include the identification, structural analysis, and functional analysis of drug-resistant HIV-1 reverse transcriptase genes. Phase I of the Physician Scientist Award will concentrate on didactic study of molecular biology, virology, and biochemistry. Virologic methods previously developed by the physician-applicant will be employed to detect drug-resistant HIV-1 clinical strains. This phase will also include intensive laboratory training in basic molecular biology and biochemical techniques including the polymerase chain reaction, cloning and sequencing of specific genes, site-directed mutagenesis, baculoviral and bacterial gene expression. In Phase II, the methodologies will be applied to investigate specific structural-functional relationships of drug-resistant HIV-1 reverse transcriptase. The studies proposed will contribute to the understanding of the pathogenesis of HIV-1 infection in patients on chronic antiretroviral therapy. Elucidation of the impact of drug therapy on the heterogeneous HIV-1 pool in man will likely influence the development of improved drugs and vaccines against HIV-1. The educational and research goals of this Physician Scientist Award will provide the physician-applicant with the foundation to independently continue basic research in molecular virology.